The cause of many diseases consists in abnormal accumulation and further crosslinking of collagen structures in the tissue. It is known in the art that crosslinking of collagen at the site of an injury, whether caused by trauma or surgical intervention, often results in scar contractures, strictures or stenosis of tubular organs, including for example the urethra, esophagus, trachea, and the like. Other effects include fibrotic adhesion to the tendon or nerve after trauma or surgical intervention, or stiffness of the joints after longer immobilization. Studies using laboratory animals, and human trials, indicate that daily administration of certain hydrophilic lathyrogens for a longer time period, reduces the disease symptoms related to collagen deposition or crosslinking.
Lathyrogens D-Pencillamine (“DPA”) and beta-aminopropionitrile (“BAPN”) block the function of the enzyme, lysyl oxidase (L.O), which initiates the formation of the first step in the process of collagen crosslinking.

Non-crosslinked collagen does not form fibrils and lacks sufficient mechanical strength to produce strictures (urethral, stenosis esophagus, trachea) or contractures (after third degree burns).
Table I summarizes certain known properties of BAPN and DPA.
TABLE ICharacteristicBAPN-FD-PAClassificationlathyrogenLathyrogen + chelating agentEffect on collagenspecific block lysylchelates copper of L.O.oxidase, irreversiblyBinds to aldehydes, preventsformation of crosslinksCleaves nonreduced Schiffbase crosslinksClinical usenoneRheumatoid Arthritis, Wilsondisease, cystinuriaIND-sclerodermaintoxication by metals(Pb, Hgperitendinous adhesionsurethral stricturesToxicity in systemicyesyesadministrationIn local administrationnonenoneInteractions with othervery specific for lysyl oxidase.metals (Cu, Fe, Zn), B6,MetabolitesIrreversible inhibitor.
It is known in the art that non-crosslinked collagen, i.e. not polymerized into collagen fibers, does not provide supporting stroma for cells and pericapillary sheath, i.e. basal lamina, in newly formed vessels. Furthermore, disintegrated collagen structure is more susceptible to degradation by the system of collagenases. As a result, treating a tumor with DPA inhibits tumor growth, and the treated structure regresses.
The clinically beneficial effects of orally administered DPA and/or BAPN are, however, marred by side toxic effects. These toxic side effects often force the discontinuation of the treatment. Nevertheless, DPA has been used clinically in systemic administration for more than forty (40) years in the treatment of Wilson disease (Cu accumulation), cystinuria, rheumatoid arthritis, scleroderma, metal poisoning and others, in spite of common occurrence of side toxic effects.
In order to mitigate the toxicity of DPA and/or BAPN, U.S. Pat. No. 4,485,088, in the name of Chvapil, teaches a method to treat fibrotic lesions by topical administration of lathyrogenic drugs, including DPA and BAPN. The '088 patent teaches a method wherein these drugs are administered locally or topically into or onto the site of the lesion. Using this treatment protocol, the dose was 100 to 200 times lower than that needed for similar effect when systemically administered. Topical administration of such lower dosages of DPA and/or BAPN did not produce local or systemic toxic effects.
Two major problems arose, however, with local administration of either lathyrogen. Firstly, these drugs need to be administered daily because they are quickly metabolized in tissues. Secondly, the strategic enzyme to be inhibited, i.e. lysyl oxidase (L.O.), is known to be rapidly resynthesized. Therefore, in order to achieve continuous inhibition of tumor growth, a stable concentration of the lathyrogen in the tissue is required. It is known in the art that after an injury the increased L.O. activity persists for 3–12 weeks, depending on the tissue affected. Therefore, daily continuous administration of the lathyrogen is required over 3 to 12 weeks post injury, depending on the type of the injury.
Applicant has discovered, however, that local intratumoral (ITI) injection of various therapeutic modalities produces the maximal concentration of the treatment within the target tissue with minimal outflow into the systemic circulation. See, Example IV, below. Therefore, repetitive local injections of one or more lathyrogens into a tumor minimize or completely avoid the occurrence of toxic side effects typical for most of chemotherapeutics or immunosuppressive drugs when administered systemically.
Several treatment options for local delivery of one or more lathyrogens exist. The simplest and most direct is injection into the tumor using a fine needle under the assistance of diagnostic imaging. Intra arterial injection is limited to those tumors comprising a recognizable artery, and is reported to result in lower delivery of the medication. Use of an implantable osmotic micropump requires surgical intervention.
Using Applicant's local injection into a tumor, the therapeutics can be delivered in a solvent, or in a polymeric delivery system. In either case, the structural characteristics of the therapeutics are important for obtaining the sustained release for a reasonable time period. These structural characteristics include molecular weight, electrical charge, and most importantly, the affinity to aqueous environment, i.e. hydrophilicity vs lipophilicity.
The use of DPA and/or BAPN, or salts VI and/or VII of these lathyrogenic compounds, for intra-tumoral injections (“ITI”) is not feasible because of high water solubility. BAPN-F comprises Compound VII wherein X− is fumarate.

Furthermore, disposing one or more of DPA, BAPN, Compound VI, and/or Compound VII in a polymeric carrier does not afford long-term release. Rather, these compounds are quickly washed out from the tissue within few hours. Therefore, Applicant chemically modified D-penicillamine or b-aminopropionitrile, the two most studied and effective representative of lathyrogenic substances, to form lipophilic derivatives. It was essential that such derivatization not block the functional groups responsible for the immediate lathyrogenic effects seen with DPA and/or BAPN.
With the exception of the '088 patent to Chvapil, use of local-topical administration of lathyrogenic substances for medical treatments is not known in the art. What is needed is a method for sustained administration of one or more lathyrogens, where those lathyrogens are released over a period of weeks following a single injection into the tissue. Both BAPN-F and DPA comprise small molecules, having molecular weights of 130 and 300 Daltons, respectively. Both compounds are also very soluble in aqueous media, such as tissue fluid. These molecular weight and solubility characteristics promote rapid diffusion of these drugs from the injection site, or fast release from a polymeric carrier. What is needed is a method to derivatize these lathyrogens to increase molecular weight and/or to reduce water solubility.